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In this week's Nature, University of California, Berkeley, researcher and CRISPR/Cas9 pioneer Jennifer Doudna and colleagues present data giving new insights into how the genome-editing technology zeroes in on its target. They found that the conformational state of the nuclease domain that cleaves target DNA strands directly controls the cutting activity. The discovery highlights a "proofreading mechanism" that serves as a final checkpoint before DNA double-strand break formation.